Exploring GVS as a display modality: signal amplitude and polarity, in various environments, impacts on posture, and with dual-tasking.

Galvanic Vestibular Stimulation (GVS) has been proposed as an alternative display modality to relay information without increasing demands on the visual or auditory sensory modalities of the wearer or in environments where those modalities cannot be used (e.g., covert night operations). We further investigated this concept with four experiments designed to test: (1) thresholds at which subjects could distinguish between different GVS current amplitudes and polarities, (2) thresholds at which different bipolar (i.e., sinusoidal waveform with current oscillating between left and right directions) current frequencies were distinguishable among room temperature, hot, cold, and windy environments, (3) effects of unipolar (i.e., sinusoidal waveform with current occurring in only the left or right direction) currents on balance performance, and (4) dual-task performance among frequency and polarity modulated GVS conditions during a concordant visual search task. Subjects reliably distinguished between current amplitudes that varied from a pedestal of ± 0.6 mA by a median of 0.03 mA (range of 0.02-0.32 mA) and between unipolar currents at a median amplitude of 0.55 mA (range of 0.32-0.83 mA). GVS frequency thresholds were robust to the environment conditions tested, with no statistical differences found. Sway and balance errors were increased with unipolar currents. GVS thresholds were not impacted by the dual-task paradigm, but the visual search scores were slightly elevated when congruently performing a polarity thresholding task. Overall findings continue to support GVS use as a display modality, but some limitations are noted, such as the use of unipolar currents under scenarios where postural control is important.

An antibody that inhibits TGF-ß1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis.

Inhibitors of the transforming growth factor-ß (TGF-ß) pathway are potentially promising antifibrotic therapies, but nonselective simultaneous inhibition of all three TGF-ß homologs has safety liabilities. TGF-ß1 is noncovalently bound to a latency-associated peptide that is, in turn, covalently bound to different presenting molecules within large latent complexes. The latent TGF-ß-binding proteins (LTBPs) present TGF-ß1 in the extracellular matrix, and TGF-ß1 is presented on immune cells by two transmembrane proteins, glycoprotein A repetitions predominant (GARP) and leucine-rich repeat protein 33 (LRRC33). Here, we describe LTBP-49247, an antibody that selectively bound to and inhibited the activation of TGF-ß1 presented by LTBPs but did not bind to TGF-ß1 presented by GARP or LRRC33. Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-ß1 that is not accessible on GARP- or LRRC33-presented TGF-ß1, explaining the antibody's selectivity for LTBP-complexed TGF-ß1. In two rodent models of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating the central role of LTBP-presented TGF-ß1 in renal fibrosis. In mice, LTBP-49247 did not have the toxic effects associated with less selective TGF-ß inhibitors. These results establish the feasibility of selectively targeting LTBP-bound TGF-ß1 as an approach for treating fibrosis.

Simultaneous and cumulative effects of tDCS on cerebral metabolic rate of oxygen in multiple sclerosis.

Introduction: Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique with simultaneous (during stimulation) and cumulative effects (after repeated sessions) on blood flow and neuronal metabolism. These effects remain mostly unclear especially in multiple sclerosis (MS). This work aims to elucidate brain metabolic and hemodynamic underpinnings of tDCS and its potential therapeutic impact in MS patients using quantitative tDCS-MRI. Methods: MS participants (n = 20; age = 45.4 ± 12.3 years, 7 males) underwent 3 T MRI scans before and after 20 daily sessions of dorsolateral prefrontal cortex (DLFPC) tDCS (2.0 mA, left anodal) paired with adaptive cognitive training (aCT). During both visits, imaging measurements of cerebral blood flow (CBF), cerebral venous blood oxygenation (Yv) and calculated cerebral metabolic rate of oxygen (CMRO2) were obtained at pre-tDCS, during-tDCS and post-tDCS. Results: At baseline, significant increase from pre- to during-tDCS was observed in CMRO2 (7.6%; p = 0.002), CBF (11.0%; p < 0.0001) and Yv (1.9%; p = 0.006). At follow up, we observed an increase in pre-tDCS CMRO2 (140.59 ± 13.83 µmol/100 g/min) compared to baseline pre-tDCS levels (128.30 ± 14.00 µmol/100 g/min; p = 0.006). Sustained elevations in CMRO2 and CBF into post-tDCS were also observed (tDCS lingering effects). Cumulative tDCS effects were observed in the form of sustained elevations in CMRO2 and CBF in pre-tDCS follow up, reaching the magnitudes measured at baseline during-tDCS. Discussion: TDCS induces an acute surge in metabolic activity persisting immediately after the stimulation is removed. Moreover, treatment composed of repeated tDCS-aCT paired sessions contributes to establishing long-lasting increases in neuronal activity.

Efficacy of non-invasive brain stimulation and neuronavigation for major depressive disorder: a systematic review and meta-analysis.

INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are increasingly used for major depressive disorder (MDD). Most tDCS and rTMS studies target the left dorsolateral prefrontal cortex, either with or without neuronavigation. We examined the effect of rTMS and tDCS, and the added value of neuronavigation in the treatment of MDD. METHODS: A search on PubMed, Embase, and Cochrane databases for rTMS or tDCS randomized controlled trials of MDD up to 1 February 2023, yielded 89 studies. We then performed meta-analyses comparing tDCS efficacy to non-neuronavigated rTMS, tDCS to neuronavigated rTMS, and neuronavigated rTMS to non-neuronavigated rTMS. We assessed the significance of the effect in subgroups and in the whole meta-analysis with a z-test and subgroup differences with a chi-square test. RESULTS: We found small-to-medium effects of both tDCS and rTMS on MDD, with a slightly greater effect from rTMS. No significant difference was found between neuronavigation and non-neuronavigation. CONCLUSION: Although both tDCS and rTMS are effective in treating MDD, many patients do not respond. Additionally, current neuronavigation methods are not significantly improving MDD treatment. It is therefore imperative to seek personalized methods for these interventions.

Intradermal infection and dissemination of Candida auris in immunocompetent and immunocompromised mouse models.

Candida auris, an emerging fungal pathogen, predominately colonizes human skin leading to serious invasive infections in humans. Though it is assumed that skin colonization can lead to invasive infection, dissemination potential of C. auris from skin to internal organs is still unknown. In this study, immunocompetent and immunocompromised mouse models of intradermal skin infection were used to compare the dissemination potential of C. auris to internal organs. Our results suggest that C. auris persists in the skin tissue of both immunocompetent and immunocompromised infected mice even at 30 days post-infection. Furthermore, C. auris can readily disseminate from skin tissue to internal organs such as the spleen and kidney as early as 24 h post-infection and was detected until 30 days post-infection. Taken together, our findings for the first time indicate that murine skin intradermally infected with C. auris can readily disseminate to internal organs and cause invasive infections. IMPORTANCE: Candida auris is a multi-drug-resistant emerging fungal pathogen colonizes the human skin and causes life-threatening infections. However, whether C. auris can disseminate from the skin to internal organs is unclear. Understanding the dissemination potential of C. auris in both immunocompetent and immunocompromised hosts is necessary to monitor susceptible individuals and to develop novel approaches to prevent and treat this emerging fungal pathogen. Using mouse models of intradermal C. auris skin infection, our findings report a novel observation that mice skin intradermally infected with C. auris can readily disseminate to internal organs leading to systemic disease. These findings help explain the colonization, persistence, and dissemination potential of C. auris in immunocompetent and immunocompromised hosts and reveal that skin infection is a potential source of invasive infection.

The Candida auris Hog1 MAP kinase is essential for the colonization of murine skin and intradermal persistence.

Candida auris , a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. Since then, systemic C. auris infections have now been reported in more than 50 countries, with mortality rates of 30-60%. A major contributing factor to its high inter- and intrahospital clonal transmission is that C. auris, unlike most Candida species, displays unique skin tropism and can stay on human skin for a prolonged period. However, the molecular mechanisms responsible for C. auris skin colonization, intradermal persistence, and systemic virulence are poorly understood. Here, we report that C. auris Hog1 mitogen-activated protein kinase (MAPK) is essential for efficient skin colonization, intradermal persistence, as well as systemic virulence. RNA-seq analysis of wildtype parental and hog1 Δ mutant strains revealed marked down-regulation of genes involved in processes such as cell adhesion, cell-wall rearrangement, and pathogenesis in hog1 Δ mutant compared to the wildtype parent. Consistent with these data, we found a prominent role for Hog1 in maintaining cell-wall architecture, as the hog1 Δ mutant demonstrated a significant increase in cell-surface ß-glucan exposure and a concomitant reduction in chitin content. Additionally, we observed that Hog1 was required for biofilm formation in vitro and fungal survival when challenged with primary murine macrophages and neutrophils ex vivo . Collectively, these findings have important implications for understanding the C. auris skin adherence mechanisms and penetration of skin epithelial layers preceding bloodstream infections. Importance: Candida auris is a World Health Organization (WHO) fungal priority pathogen and an urgent public health threat recognized by the Centers for Disease Control and Prevention (CDC). C. auris has a unique ability to colonize human skin. It also persists on abiotic surfaces in healthcare environments for an extended period of time. These attributes facilitate the inter- and intrahospital clonal transmission of C. auris . Therefore, understanding C. auris skin colonization mechanisms are critical for infection control, especially in hospitals and nursing homes. However, despite its profound clinical relevance, the molecular and genetic basis of C. auris skin colonization mechanisms are poorly understood. Herein, we present data on the identification of the Hog1 MAP kinase as a key regulator of C. auris skin colonization. These findings lay foundation for further characterization of unique mechanisms that promote fungal persistence on human skin.

Using Home-based, Remotely Supervised, Transcranial Direct Current Stimulation for Phantom Limb Pain.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low-amplitude direct currents to alter cortical excitability. Previous trials have established the safety and tolerability of tDCS, and its potential to mitigate symptoms. However, the effects are cumulative, making it more difficult to have adherence to the treatment since frequent visits to the clinic or outpatient center are required. Moreover, the time needed for transportation to the center and the related expenses limit the accessibility of the treatment for many participants. Following guidelines for remotely supervised transcranial direct current stimulation (RS-tDCS) implementation, we propose a protocol designed for remotely supervised and home-based participation that uses specific devices and materials modified for patient use, with real-time monitoring by researchers through an encrypted video conferencing platform. We have developed detailed instructional materials and structured training procedures to allow for self- or proxy-administration while supervised remotely in real time. This protocol has a specific design to have a series of checkpoints during training and execution of the visit. This protocol is currently in use in a large pragmatic study of RS-tDCS for phantom limb pain (PLP). In this article, we will discuss the operational challenges of conducting a home-based RS-tDCS session and show methods to enhance its efficacy with supervised sessions.

Amplitude-determined seizure-threshold, electric field modeling, and electroconvulsive therapy antidepressant and cognitive outcomes.

Electroconvulsive therapy (ECT) pulse amplitude, which dictates the induced electric field (E-field) magnitude in the brain, is presently fixed at 800 or 900 milliamperes (mA) without clinical or scientific rationale. We have previously demonstrated that increased E-field strength improves ECT's antidepressant effect but worsens cognitive outcomes. Amplitude-determined seizure titration may reduce the E-field variability relative to fixed amplitude ECT. In this investigation, we assessed the relationships among amplitude-determined seizure-threshold (STa), E-field magnitude, and clinical outcomes in older adults (age range 50 to 80 years) with depression. Subjects received brain imaging, depression assessment, and neuropsychological assessment pre-, mid-, and post-ECT. STa was determined during the first treatment with a Soterix Medical 4×1 High Definition ECT Multi-channel Stimulation Interface (Investigation Device Exemption: G200123). Subsequent treatments were completed with right unilateral electrode placement (RUL) and 800 mA. We calculated Ebrain defined as the 90th percentile of E-field magnitude in the whole brain for RUL electrode placement. Twenty-nine subjects were included in the final analyses. Ebrain per unit electrode current, Ebrain/I, was associated with STa. STa was associated with antidepressant outcomes at the mid-ECT assessment and bitemporal electrode placement switch. Ebrain/I was associated with changes in category fluency with a large effect size. The relationship between STa and Ebrain/I extends work from preclinical models and provides a validation step for ECT E-field modeling. ECT with individualized amplitude based on E-field modeling or STa has the potential to enhance neuroscience-based ECT parameter selection and improve clinical outcomes.

Effect of non-invasive spinal cord stimulation in unmedicated adults with major depressive disorder: a pilot randomized controlled trial and induced current flow pattern.

Converging theoretical frameworks suggest a role and a therapeutic potential for spinal interoceptive pathways in major depressive disorder (MDD). Here, we aimed to evaluate the antidepressant effects and tolerability of transcutaneous spinal direct current stimulation (tsDCS) in MDD. This was a double-blind, randomized, sham-controlled, parallel group, pilot clinical trial in unmedicated adults with moderate MDD. Twenty participants were randomly allocated (1:1 ratio) to receive "active" 2.5 mA or "sham" anodal tsDCS sessions with a thoracic (anode; T10)/right shoulder (cathode) electrode montage 3 times/week for 8 weeks. Change in depression severity (MADRS) scores (prespecified primary outcome) and secondary clinical outcomes were analyzed with ANOVA models. An E-Field model was generated using the active tsDCS parameters. Compared to sham (n = 9), the active tsDCS group (n = 10) showed a greater baseline to endpoint decrease in MADRS score with a large effect size (-14.6 ± 2.5 vs. -21.7 ± 2.3, p = 0.040, d = 0.86). Additionally, compared to sham, active tsDCS induced a greater decrease in MADRS "reported sadness" item (-1.8 ± 0.4 vs. -3.2 ± 0.4, p = 0.012), and a greater cumulative decrease in pre/post tsDCS session diastolic blood pressure change from baseline to endpoint (group difference: 7.9 ± 3.7 mmHg, p = 0.039). Statistical trends in the same direction were observed for MADRS "pessimistic thoughts" item and week-8 CGI-I scores. No group differences were observed in adverse events (AEs) and no serious AEs occurred. The current flow simulation showed electric field at strength within the neuromodulation range (max. ~0.45 V/m) reaching the thoracic spinal gray matter. The results from this pilot study suggest that tsDCS is feasible, well-tolerated, and shows therapeutic potential in MDD. This work also provides the initial framework for the cautious exploration of non-invasive spinal cord neuromodulation in the context of mental health research and therapeutics. The underlying mechanisms warrant further investigation. Clinicaltrials.gov registration: NCT03433339 URL: https://clinicaltrials.gov/ct2/show/NCT03433339 .

Use of mini implants for the two-implant retained mandibular overdenture: A prospective study.

Background: The two-implant retained mandibular overdenture utilizing nonsplinted implants is a proven treatment modality for completely edentulous patients. However, a lacuna still exists regarding the suitability of mini dental implants for this purpose. The purpose of the study was to evaluate implant stability and crestal bone loss in single-piece mini dental implants loaded with immediate or conventional loading protocols to retain a mandibular overdenture. Method: Twenty-four completely edentulous patients were rehabilitated using conventional maxillary complete denture and a mandibular two-implant retained overdenture utilizing nonsplinted single piece mini implants. The implants were loaded with immediate or conventional loading protocols. Implant stability (with Periotest TM) and crestal bone loss (with radiovisiograph and radiographic grid) were evaluated at the time of loading and at one, two, and six months after loading. Statistical analysis was done with the Independent Samples "t" test and One-Way ANOVA. Results: Mean Periotest Values observed were significantly more negative in implants loaded with the conventional loading protocol. Crestal bone loss was significantly lesser in the immediate loading protocol but was still higher than the requisite 1.5 mm postulated by established criteria. Conclusion: Two single-piece nonsplinted mini implants may be sufficient to retain a mandibular overdenture utilizing the immediate loading protocol. Further studies with a longer duration of observation and larger sample size are required.